1. Chronic Viral Hepatitis:
Associate Prof Dr Meltem Ergun
Yeditepe University
Department of Gastroenterology

2. Objective To identify the etiologic agents of chronic viral hepatitis
Know the
Pathophysiology,
Clinical presentation
Diagnosis,
Evaluation and
Management of chronic viral hepatitis

3. Clinical Terms
Hepatitis: inflammation of liver; presence of inflammatory cells in the liver
Acute Viral Hepatitis: symptoms last less than 6 months
Chronic Hepatitis: Inflammation of liver for at least 6 months
Cirrhosis: a late stage of progressive hepatic fibrosis characterized by distortion of the hepatic architecture and the formation of regenerative nodules.
Fulminant Hepatitis: severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of preexisting liver disease

6. Acute viral hepatitis etiologic agents

7. Acute viral hepatitis Hepatitis A Hepatitis B Hepatitis C Hepatitis D
Hepatitis E

8. Hepatitis A Common cause of acute hepatitis
Single-stranded, positive-sense, linear RNA enterovirus (Picornaviridae)
Transmission fecal-oral route; Contaminated water and food
The incubation period of hepatitis A virus is 2-7 weeks,
AST & ALT levels usually return to reference ranges over 5-20 weeks.
High risk  Travellers: vaccinations; passive immunoglobins given to those exposed
Mild self-limited disease and confers lifelong immunity to hepatitis A virus. Chronic infection with hepatitis A virus does not occur.
HAV: IgM anti-HAV: positive at the time of onset of symptoms; results remain positive for 3-6 months after the primary infection
Treatment: supportive

9. Hepatitis E Hepatitis E virus (HEV) RNA virus of the genus Hepevirus
Enterically transmitted infection; fecal-oral route, typically self-limited
Most outbreaks occur in developing countries.
Symptoms of acute hepatitis
Incubation period of hepatitis E virus is 2-9 weeks
Case fatality rate is 4% Pregnancy mortality ↑

10. Clinical Evaluation: Acute Viral Hepatitis
1. Prodromal phase:
Patients experience anorexia, nausea, vomiting, alterations in taste, arthralgias, malaise, fatigue, urticaria, and pruritus. Some develop an aversion to cigarette smoke.
When seen by a health care provider during this phase, patients are often diagnosed as having gastroenteritis or a viral syndrome.
2. Icteric Phase
Jaundice, Patients may note dark urine, followed by pale-colored stools.
In addition to the predominant gastrointestinal symptoms and malaise, patients become icteric and may develop right upper quadrant pain with hepatomegaly.
Severe cases may result in Fulminant Hepatitis:
Hepatic Encephalopathy: B/L asterixis, palmar erythema
Hepatorenal syndrome
Bleeding diathesis

11. Chronic Hepatitis
HBV
HCV
HDV

12. Hepatitis: B & D

13. Hepatitis B(HBV)--EPIDEMIOLOGY
HBV is a DNA virus that belongs to the hepadnavirus family.
1/3 of population of the World has had hepatitis B infection.
400 million people are chronic  HBV carriers.
HBV is the cause of 60% to 80% of worldwide Hepatocellular Carcinoma(HCC).
500,000 to 1 million deaths worldwide are attributed to it.
5% to 10% of all liver transplants are attributed to HBV.
In Turkey %80 transplants are attributed to HBV.

14. Risk Groups IV drug users People receiving multiple blood transfusions
Sexual promiscuity
People in contact with HBV carriers
Travelers to endemic areas of South America, Southern Asia, and Africa
Resident and employees of residential care facilities
Health Care Workers

15. Pathophysiology Transmission 3 main ways:
Parenterally/percutaneous route----IV Drug Users, needle sticks, Hemodialysis patients
Sexually
Vertical/ Perinatal route (TURKEY)

16. Serology HBsAg surface antigen Present in acute or chronic infection
Detectable 1 to 2 weeks after infection
HBeAg
Appears shortly after HBsAg
Indicates viral Replication and Infectivity
HBsAB(Anti-HBS)
Present after vaccination or clearance of HBsAg(Usually 1 to 3 months)
Indicates immunity to HBV
Hb core Antibody  (IgM anti-Hbc or IgG anti-HBc)
Only Serological marker of HBV during "Window Period"

18. HBV DNA <2000 Hbs ag+ HBV DNA >2000 Hbe ag - HBV DNA >2000
Inactive carrier every 6 months ALT AFP USG HBV DNA
HBV DNA <2000
Hbs ag+
HBV DNA >2000
Chronic hepatitis B
bx and treatment
Hbe ag -
HBV DNA >2000
Immune tolerant phase
Hbe ag +

21. Clinical Presentation
Acute Hepatitis B - less than 6 months; Based on significant aminotransferase activity due to necro inflammatory injury
 Symptoms are often non-specific symptoms such as myalgia, malaise , nausea, fatigue , pruritus, abdominal pain, RUQ, jaundice
 Fulminant Hepatitis--Acute HBV results in Liver Failure
Chronic Hepatitis B - greater than 6 months; Based  on grade, stage, and etiology. Fibrosis and Necroinflammatory processes; can last for  decades
Immune tolerant--High viral replication, NL liver enzymes, low inflammation and fibrosis. Seen in children or those affected early in life.
Immune active--High Liver enzymes and High HBV DNA and HBeAg, Active Replication
Carrier State with low replication
Seroconversion from HBeAg to HBeAB
Low HBV levels, NL liver enzymes, Reduced Liver inflammation
Low risk for developing of HCC

22. Clinical Presentation cont.
Chronic HbeAg negative
HBV DNA high, Liver enzymes high, No HbeAg
Seen in late phase of HBV
Resolution
Viral clearance of HBV DNA

23. Diagnosis Serology Liver Chemistry tests
AST, ALT, ALP, and total Bilirubin
Histology--Immunoperoxidase staining
HBV Viral DNA--Most accurate marker of viral REPLICATION
Liver Biopsy--to determine grade(Inflammation) and stage(Fibrosis) in chronic Hepatitis

25. Progression Incubation Period: 30-180 days
Acute HBV Infection:  90% resolve by themselves; less than 1% develop fulminant hepatitic failure
Chronic HBV Infection: 2-10% progress to chronic state
90% in children less than five progress to chronic state
Risk of Liver  Cirrhosis:  5 year accumulation risk of 8% to 20%
5% to 10% of people progress to HCC with or without preceding cirrhosis; less than 5%  achieve  a chronic carrier state

26. Treatment Strong Agents: Interferon: Not very effective in Genotype B
Nucleoside Analogues -- Lamivudine, Entecavir, Telbivudine
Method of action is the inhibition of viral reverse transcriptase
WEAK AGENTS:
Lamivudine
Dose :  100 mg PO q daily
Good for reducing the risk of progression to hepatic decompensation in patients with cirrhosis or advanced fibrosis
Pregnancy category B--Not teratogenic in animal studies and successful use with pregnant women
Problem: High rates of resistant mutations
Telbivudine
Dose: 600mg q daily
Worse resistant profile than Entecavir
Strong Agents:
Entecavir – 1st line
0.5 to 1mg PO
very effective; low resistance and greater than 90%  HBV DNA clearance rate in HBeAG positive Px's.
more effective than lamivudine
Tenofovir:
Dose: 300mg qd
Highly effective with low resistance
Well tolerated
Interferon: Not very effective in Genotype B

29. Prophylaxis HBV Vaccine
Indicated for everyone and especially those in high risk groups
IM injection at 0,1,6 months in infants and adults
Response greater than 90% after 3rd dose
HBV Pregnant Mothers
Give 1st dose of Hip B vaccine and Hip B Immunoglobulin(HBIG)  o.5 ml within 12 hours of birth.
2nd dose at 1 month, 3rd at 6 months
Recheck at 12 months for active infection
95% lifetime immunity
Not Done---leads to 90% chronic HBV
Transmitted through birth canal  during birth or through umbilical cord.
Others i.e. those receiving a needle stick
Should receive 0.04 to 0.7 ml/kg  of HBIG and 1st dose vaccine within 48  and no later than a week.

30. Transplant
Last resort for  those with advanced Liver Disease and HCC due to infection 

31. HEPATITIS D Transmission
Only as co-infection with acute HBV or with superinfection in chronic HBV carrier
Requires outer envelope of HBsAG for replication and transmission
Can progress to chronic disease
Incubation Period 30to 150 days
Serology
Hepatitis D antibody  (Anti-HDV)
Indicates HDV superinfection
Ab not always present in acute infection---requires repeat testing

32. HEPATITIS D Risk Factors - Same high risk groups as those for Hip B
Prevention - Avoidance of Hip B and/or Hip B vaccine
DX - HDV antigen in serum or finding Ab to HDV antigen
Clinical
Coinfection-self limited
Superinfection-acute HBV carriers present with severe acute hepatitis infection  w/ increased risk for HDV infection.
                 
Fatality Rate - 2% to 10%
Cirrhosis – Fast
TX:IFN-alpha

33. A hepatitis panel is ordered for a 27 year old female as part of a routine workup for abdominal pain.
Results of serological testing a negative for HBeAg - and HBsAg -,
HBsAb + and IgG HBcAb +.
The patient has been exposed to Hep B.
Patient has recovered
Patient is in acute infective disease state
Window period
Chronically infected
Patient was never infected

34. Imaging Studies
No specific imaging studies needed for diagnosis
Obtain the appropriate diagnostic imaging studies (eg, ultrasound, CT) if the differential diagnosis favors gallbladder disease, biliary obstruction, or liver abscess.
Liver biopsy usually in cases of:
o The diagnosis is uncertain.
o Other coinfections or disease may be present.
o The patient is immunocompromised.
o Asses severity of chronic hepatitis B or chronic hepatitis C.
Histologic Findings
Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis.

35. LFT: Elevation of serum transaminases not diagnostic, but useful
ALT elevated more than AST
Acute Hepatitis: ALT > 1000
Chronic HCV: ALT is generally x1,5-2 ULN
* Urine analysis: presence of bilirubin.
* Serum bilirubin: Total bilirubin may be elevated in infectious hepatitis. Bilirubin levels higher than 30 mg/dL indicate more severe disease.
* Alkaline phosphatase: if elevated significantly, consider abscess or biliary obstruction.
* Prothrombin time (PT) if prolonged  impaired synthetic function of the liver.
* BUN & serum creatinine  decreased renal function suggests fulminant hepatic disease.
* Serum ammonia in patients with AMS or other evidence of hepatic encephalopathy.
* CBC: lymphocytosis
Lab Studies:

36. Hepatitis C
Spherical, enveloped, single-stranded RNA virus (Flavivirus genus)
Incubation period: 7-8 wks
170 million infected worldwide
Major cause of chronic hepatitis in U.S.
More common in Hispanic, AA population; females have better outcome
Parenteral Transmission: IV drug users
Most common indication for liver transplantation
1.8% of US positive for antibodies
Orthotopic liver transplantation refers to a procedure in which a failed liver is removed from the patient's body and a healthy donor liver is transplanted into the same location. The procedure is the most common method used to transplant livers.

37. Clinical Evaluation: Chronic Hepatitis C
Occurs after acute Hepatitis in >80% of people with HCV
Some are asymptomatic, or have mild symptoms; others may only present with late complications (cirrhosis/HCC)
Categorized based on grade of inflammation, stage of fibrosis, and etiology of disease

38. Hepatitis C
Usually clinically mild, does not cause significant acute illness
Fluctuating elevations of AST & ALT
20% likelihood of developing cirrhosis
50% likelihood of developing chronic hepatitis
Incubation period: days, with symptoms developing anywhere from 5-12 weeks after exposure.

39. Diagnosis: HCV
HCV: Anti-HCV; cannot distinguish acute from chronic infection
may appear 3 – 5 months after infection
PCR: used to detect viral RNA  HCV
80% of cases: patients are asymptomatic and do not develop icterus.
Treatment: Interferon alpha, Ribavirin; PEG-IFNs (better sustained absorption, a slower rate of clearance, and a longer half-life than those of unmodified IFN)
+protease± polymerase inhibitors (sofosbuvir+simeprevir)

40. A 61 yo F is brought to the ER, drowsy and disoriented, only able to follow simple commands. On PE, her abdomen is distended and non-tender and she is jaundiced. In her purse, the physician finds prescriptions for peginterferon and ribavirin. When asked to raise her hands, the physician notes a coarse tremor. Lab values show ALT = 93U/L, AST = 89U/L, total bilirubin = 3.1 mg/dL, and ammonia = 124microg/dL. What is the most likely diagnosis? A. Bleeding esophageal varices B. Hepatic encephalopathy C. Hepatocellular carcinoma D. Hepatorenal syndrome E. Spontaneous bacterial peritonitis

41. Other Causes of Hepatitis
Alcoholic Hepatitis
Drug induced Hepatitis
Autoimmune Hepatitis
Ischemic Hepatitis